The Convergence of Therapeutic Drug Monitoring and Pharmacogenetic Testing to Optimize Efavirenz Therapy

Abstract

The aim of this study was to show the benefits of combining therapeutic drug monitoring (TDM) and pharmacogenetic analyses to optimize efavirenz (EFV) therapy. Patients were selected to minimize nongenetic differences between patients: 32 HIV adherent patients without drug interactions treated with an EFV nonindividualized dose over at least 1 year and included in a TDM program were genotyped according to minimum steady-state concentrations (C ss min). The EFV plasma concentrations (n = 158) were quantified by high-performance liquid chromatography-ultraviolet, and genetic polymorphisms were analyzed using the PHARMAchip. Central nervous system side effects were assessed systematically. Genetic polymorphisms were detected in 79.2% of patients with EFV Css min outside the therapeutic range (1-4 mg/L), showing the high diagnostic efficacy of combining TDM with pharmacogenetic testing. CYP2B6 (516 G>T) polymorphisms were associated with a significant decrease in EFV plasma clearance in 80% of the poor metabolizer patients (G/T, T/T). All homozygous patients had C ss min greater than 4 mg/L, 75% of them showing central nervous system side effects. For such patients, pharmacogenetic testing with TDM could be advantageous because the polymorphism is a determinant of these circumstances and TDM would allow reductions in dose to be specified without assuming an equal dose for any given genotype. In fact, poor metabolizer patients required less than a 600 mg standard starting dose, implying that if CYP2B6 screening were available, EFV therapy could be started at 400 mg and later TDM-individualized. The results of this study clarify the genotype versus phenotype debate for optimizing drug therapy. Pharmacogenetic testing together with TDM links genotype to phenotypic differences in drug concentrations and adverse events, providing additional support for dosage adjustment and a more efficient use of both approaches. As genotype screens become cheaper, and in combination with TDM, adjusting dosages in the light of genetic polymorphisms will become a reality.

Liver Enzyme Abnormalities and Associated Risk Factors in HIV Patients on Efavirenz-Based HAART with or without Tuberculosis Co-Infection in Tanzania

“…Recently the combined use of therapeutic drug monitoring (TDM) with pharmacogenetic testing is advocated to optimize efavirenz therapy [52]. Regular TDM practice is not feasible in resource-limited countries like Tanzania.…”

PharmGKB summary

“…EFV autoinduction is also influenced by a patient’s genotype; for example, patients with the CYP2B6 * 1 allele may exhibit long-term EFV autoinduction [33, 34]. In selected situations, therapeutic drug monitoring of antiretroviral therapy may help to address these issue by individualizing dosage to minimize side effects while maintaining antiviral efficacy [31, 35], although it is important to note that EFV is often co-formulated in a fixed dose as part of an anti-viral regimen, adding a layer of complexity to individualization of dosage.…”

“…It has been proposed that CYP2B6 genotyping could be used as a screen to identify individuals who may be either slow or fast metabolizers of EFV and may benefit the most from early therapeutic drug monitoring (TDM), in order to optimize dosage as a function of exposure before or during the initiation of drug therapy [35, 46]. For example, one retrospective study reported that therapeutic dose monitoring and dose reduction in 31 patients with one or two 516 T alleles from a standard 600 mg/day dose of EFV to 400 mg/day, reduced the mean EFV C min (5.7 +/−3.4 mg/l at 600 mg/day) to within therapeutic range (2.39 +/− 1.28 mg/l at 400 mg/day) [47].…”

Therapeutic Drug Monitoring of Antiretroviral Drugs in the Management of Human Immunodeficiency Virus Infection

“…As new ARV drugs are developed and newer techniques become more widely available, the approach to TDM in the management of HIV is constantly changing [22,64]. TDM of ART requires a multidisciplinary approach, including an infectious disease specialist, a clinical pharmacist, a TDM specialist, a virologist and in the future perhaps a geneticist, to fully integrate TDM into optimal clinical management of the individual HIV-infected patient.…”